Alpha-phenyl-alpha-(2-pyridyl)-arylones



United States Patent 3,157,666 a-PHENYL-a-(2-PYRIDYL)'-ARYLONES HoraceA. De Wald, Roger D. Westland, and John R. Dice, Ann Arbor, Mich,assignors to Parke, Dav s 81 Company, Detroit, Mich, a corporation ofMichigan No Drawing. Filed Mar. 11, 1963, Ser. No. 264,080

9 Claims. ((31.260-297) The present invention relates to ketonecompounds. More particularly, it relates to u-phenyI-a-(Z-pyridyI)substituted acetophenone compounds which can be represented in free baseform by the formula cis and trans isomers In any particular compound ofthe invention, one of the indicated tautomeric forms, that is theketone, the cis enol or the trans enol, may be favored by such factorsas acidic or basic conditions or solvent. For reasons of convenience,the compounds of the invention are consistently formulated and named ashaving the ketone structure but because of the equilibrium state whichcan exist among the tautomeric forms, it will be appreciated that theketone structure includes the tautomers as Well. In accordance with theinvention, compounds of the foregoing formula are produced by reacting acompoun which can be represented by theformula with a strong acid or astrong-base in a hydroxylic medium; where Ar is as defined before. Theterms strong acid and strong base are used in a relative sense and imean an acid or a'baseof suificient strength to convert the iminegroupjto a ketone-gr'oup under feasible reaction Nice conditions. Thepreferred reagents for carrying out this process are dilute orconcentrated mineral acids such as hydrochloric acid, sulfuric acid andphosphoric acid. However, other relatively strong acids such astrifluoro acetic acid, benzenesulfonic acid, p-toluenesulfonic acid,formic acid and acetic acid, as well as relatively strong bases such asalkali metal and alkaline earth metal hydroxides, oxides and carbonatescan also be used. The

preferred hydroxylic medium is Water or a mixture of water with anothersolvent such as an alkanol, ether, or dimethylformamide. Otherhydroxylic media such as lower alkanols or mixtures of lower alkanolswith various solvents can be used. The acidic or basic reagent is preferably employed in excess of the calculated amount and the presence ofa substantial excess facilitates the reaction. The substance beingreacted with the acidic or basic reagent, although for conveniencerepresented in the foregoing formula as having an imine structure, canalso exist in equivalent tautomeric forms, the cis enamine and the transenamine. In the process described, the starting material can, of course,be used as an equivalent tautomeric form. The reaction proceeds at asatisfactory rate under moderate reaction conditions, and typically iscarried out at a temperature from 0-100" C. with an acidic reagent andfrom 0-50 C. with a basic reagent, for from 5 minutes to 24 hours. Forexample, using mineral acid the reaction is normally substantiallycomplete within 24 hours at room temperature or within a few minutes atC., whereas with somewhat weaker organic acids a higher temperature orlonger reaction time is used. Depending upon specific conditions, thereaction product is formed initially in either free base or salt formand is isolated in either free base or salt form following pH adjustmentas required.

The imine compounds employed as starting materials in the foregoingprocess can be prepared by reacting a benzonitrile compound of theformula with a reactive metal derivative such as the lithium derivativeof Z-benzylpyridine under anhydrous conditions, followed by mildhydrolysis'of the reaction mixture, as with water or ammonium chloridesolution; where Ar is as defined before. Theimine compounds employed asstarting materials can be" produced in situ and used without isolationif desired;

Also in accordance with the invention, compounds of the formulaOH-iil-Ar are produced by reacting a compound of the formula "Someexamples of suitable reactive metal derivatives of 2 -benzylpyridine arethe lithium, sodium, potassium, calcium, and magnesium halidederivatives. T he preferred. reactive metal derivatives are the alkalimetal derivatives 'which can be prepared by reacting 2-benzylpyridinewith f such reagents as phenyllithium, butyllithium, lithium pi-'peridide, sodium diisopropylamide, or potassium diiso propylamide. Themagnesium halide derivatives cangbe prepared by reacting an alkali metalderivative with a magnesium halide. Of the preferred alkali metalderivatives, the lithium derivative is the most suitable. When Z is ahydrocarbonoxy group, the starting material in which it appears is anester. The hydrocarbonoxy group is preferably lower alkoxy. When Z is ahalogen, the starting material in which it appears is an acid halide.The preferred halogen is chlorine, The first phase of the process iscarried out by reacting the compound with a reactive metal derivative,preferably an alkali metal derivative, of 2-benzylpyridine in anon-hydroxylic solvent. The starting materials are normally employed inapproximately equimolar quantities although if desired an axcess ofeither can be used. Some examples of suitable non-hydroxylic solventsare ether, ether-hydrocarbon mixtures, tetrahydrofuran, and diethyleneglycol dimethyl ether. If desired, the reactive metal derivative ofZ-benzylpyridine can be formed directly in the reaction mixture and usedwithout isolation. Depending on the particular reactants used, thereaction of the ester or acid halide with the reactive metal derivativeof 2- benzylpyridine is carried out at temperatures between 80 and 100C. or the reflux temperature of the solvent, lower temperatures beingpreferred when the reactive metal derivative is a magnesium halidederivative and temperatures above room temperature being preferred inother cases. The time required for substantial completion of thereaction varies between about one hour and four days. When using thelithium derivative of 2 benzylpyridine and a compound in which Zrepresents methoxy, in refluxing ether, a reaction time of 12 hours isadequate. The desired product is then obtained following hydrolysis ofthe reaction mixture with water or other aqueous medium. The product isisolated in either free base or salt form following pH adjustment asrequired.

The compounds of the invention are preferably produced and used in theforms of their free bases. However, they are also capable of formingsalts with acids and bases and can be produced and used in such saltforms if desired. The salt forming capabilities of the free bases of theinvention vary because of such factors as hydrogen bonding andpossibilities for internal salt formation. The free bases of theinvention form acidaddition salts by reaction with relatively strongacids, preferably under anhydrous conditions. However, theability toform acid-addition salts is limited and in some cases the free baseitself separates from a moderately acidic medium. The free bases of theinvention also form salts with strong bases such as sodium hydroxide andpotassium hydroxide, these salts being salts of the enolic forms. Theforegoing salts with acids and bases tend to revert to the free basesexcept when maintained under quite strongly acidic or alkalineconditions but in Example 1 A solution of g. of2-[a-(o-methylbenzimidoyhbenzyl]pyridine in 500 ml. of 0.1 Nhydrochloric acid is maintained at 37 C. for 24 hours. Theu-phenyl-a-(Z- pyridyl)-2-methylacetophenone which separates iscollected on a filter, washed with water and dried; M.P.

By the foregoing general procedure, the product obtained from2-[a-(o-ethylbenzimidoyl)benzyl1pyridine is 4-u-phenyl-a-(2-pyridyl)-2-ethylacetophenone; M.P. 11'8- 121 C.

A solution is prepared by dissolving 4.4 g. ofa-phenyla-(Z-pyridyl)-2-methylacetophenone in 25 ml. of warm 6 Nsulfuric acid. The solution is allowed to cool slowly and the sulfatesalt which separates is collected on a filter; M.P. l7918l C. followingcrystallization from .methanol-ether.

The starting materials are obtained as follows. A solution ofphenyllithium is prepared by adding a solution of 187 g. of bromobenzenein 500 ml. of anhydrous ether with vigorous stirring to 17 g. of lithiumchips in 500 ml. of anhydrous ether. The mixture is maintained underreifux by regulating the rate of addition and is stirred for 30 minutesafter the addition is complete. With continued stirring, a solution of210 g. of Z-benzylpyridine in 500 ml. of anhydrous ether is added to thesolution of phenyllithium at such a rate that the ether is maintained atreflux. The reaction mixture which now contains the lithium derivativeof Z-benzylpyridine is stirred for one more hour and then a solution of117 g. of o-methylbenzonitrile in 200 ml. of anhydrous ether is added.The mixture is heated under reflux for 12 hours, chilled, and stirredwith 300 ml. of saturated aqueous ammonium chloride solution. The etherlayer is separated, dried over anhydrous magnesium sulfate, andconcentrated to give an oily residue of 2-[a-(omethylbenzimidoyl)benzyl]pyridine; B.P. 180-190 C. at 0.3 to 0.5 mm. Forfurther purification, the compound can be crystallized from methanol;M.P. 7680 C. By the same general procedure, using 12.5 g. ofphenyllithium and 22 g. of 2 benzylpyridine, and with the substitutionof 15.7 g. of o-ethylbenzonitrile for the o-methylbenzonitrile, theproduct obtained is 2- [a-(o-ethylbenzimidoyl)benzyl] pyridine; M.P.98-100 C. after crystallization from methanol.

Example 2 A solution of 21.7 g. of 2-[a-(o-chlorobenzimidoyD-benzyl]pyridine in 150 m1. of phosphoric acid is maintained at 25 C. for20 hours and then poured with stirring into 2 liters of ice water. Theinsoluble a-phenylw(2-pyridyl)-2-chloroacetophenone which separates iscollected on a filter, washed with water and dried; M.P. 135-137 C.

By the foregoing procedure, with the substitution of the same quantityof Z-[ix-(o-bromobenzimidoyl)benzyl]- pyridine for the2-[a-(o-chlorobenzimidoyl)benzyl]pyridine, the product obtained isa-phenyI-a-(Z-pyridyI)-2- bromoacetophenone; M.P. 141-1425 C.

The starting materials are obtained as follows. 23 g. ofZ-benzylpyridine is added to a solution of phenyllithium (prepared from2.1 g. of lithium and 23 g. of bromobenzene in ml. of ether) and themixture is heated under reflux for one-half hour. A solution of 16.5 g.of ochlorobenzonitrile in 100 ml. of ether is added and the mixture isheated under reflux for three more hours, cooled, and stirred with 250ml. of ice water. The ether solution is separated, dried, and evaporatedunder reduced pressure to give a residue of crude2-[a-(o-chlorobenzimidoyl)benzyl]-pyridine. For purification the productcan be dissolved in ether, the solution chromatographed on alumina andthe solid fractions recovered from the eluates; recrystallized frommethanol, M.P. 86-88 C.

A solution of 15.3 g. of diethylamine in 50 ml. of

' anhydrous ether is added to a solution of 49 g. of 23.7%

n-butyllithium (in heptane) in 75 ml. of anhydrous ether. The mixture isstirred for 30 minutes and then a solution of 3 1.8 g. of2-benzylpyridine in 50 ml. of ether is added with external cooling tomaintain the temperature at about 25 C. Thirty minutes later, 32.7 g. ofo-bromobenzonitrile in 50 ml. of ether is added and the mixture isstirred for 2% days and decomposed by stirring with saturated ammoniumchloride solution. The ether layer is separated, dried, and evaporatedto give a residue of imidoyl) -benzyl] pyridine.

, solution.

2-[ct-(o-bromobenzimidoyl)-benzyl]pyridine; M.P. 107- 109 C. aftercrystallization from methanol.

Example 3 A mixture of 5 g. of 2-[a-(o-methoxybenzimidoyl)- benzyl]pyridine and 25 ml. of concentrated hydrochloric acid is heated at90-100" C. for ten minutes, cooled, diluted with 50 ml. of water andneutralized with 50% sodium hydroxide solution. The mixture is thenextracted with 50 ml. of chloroform and the chloroform extract isseparated, washed with water, dried, and evaporated to givea-phenyl-u-(2-pyridyl)-2-methoxyacetophenone; M.P. 104-109 C. followingcrystallization from methanol.

The starting material is obtained as follows. 23 g. of Z-benzylpyridineis added to a solution of phenyllithium (prepared from 2.1 g. of lithiumand 23 g. of bromobenzene in 100 ml. of ether) and the mixture is heatedunder reflux for one-half hour. A solution of 1 6 g. ofo-methoxybenzonitrile in 100 ml. of ether is added and the mixture isheated under reflux for three more hours,

cooled, and stirred with 250 ml. of ice water. The ether solution isseparated, dried, and evaporated under reduced pressure to give aresidue of crude 2-[oc-(o-methoxybenz- For purification the product canbe dissolved in ether, the solution chromatographed 'on alumina and thesolid fractions recovered from the eluates; recrystallized frommethanol, M.P. 75-79" C.

Example 4 A mixture of 16 g. of 2-[ot-(o-methylthiobenzimidoyl)-benzyl]pyridine and 50 ml. of concentrated hydrochloric acid is heatedat 90-100" C. for 15 minutes, cooled, diluted with water, neutralizedwith 40% sodium hydroxide solution, and extracted with chloroform. Thechloroform extract is washed with water and with saturated sodiumchloride solution, dried over magnesium sulfate, filtered, andevaporated under reduced pressure to giveu-phenyl-u-(2-pyridyl)-2-(methylthio) acetophenone; M.P. 155l57 C.following trituration with hot methanol.

The starting material is' obtained as follows. 23 g. of 2-benzylpyridineis added to a solution of phenyllithiurn (prepared from 2.1 g. oflithium and 23 g. of bromobenzene in 100 ml. of ether) and the mixtureis heated under reflux for one-half hour. A solution of 18 g. ofo-"nethylthiobenzonitrile in 100 ml. of ether is added and the mixtureis heated under reflux for 3 more hours, cooled, and stirred with 250ml. of ice water. 'Theinsoluble Z-[a (omethylthiobenzimidoyl)benzylpyridine which separates is collected on afilter; M.P. 163-165 C. following crystallization from methanol.

Eample 5 A mixture of 27 g. of 2-[ot-(1-naphthirnidoyl)benzyl]-pyridine, 100 ml. of concentrated hydrochloric acid and 50 ml. ofethanol is heated at 90-l00 C. for three hours. The ethanol is removedby distillation under reduced pressure and the remaining aqueous mixtureis diluted with ice water and made basic with 50% sodium hydroxide Themixture is extracted with chloroform and the chloroform extract isseparated, washed with water, dried, and concentrated to give crudeu-phenyl-u-(2-pyridyl)-1-acetonaphthone; M.P. l29-132 C. followingcrystallization from ethanol. This compound can also be named asl-naphthyl Ot-(Z- yridyDbenZyl ketone.

A mixture of g. of 2-[a-(1-naphthimidoyl)benzyl]- pyridine, 100 ml. ofethanol, and 20 ml. of 50% sodium hydroxide solution is stirred at 40 C.for 24 hours. Most of the ethanol is removed by distillation underreduced pressure below 35 C. The remaining mixture is dilluted with icewater, neutralized with dilute hydrochloric acid and extracted withchloroform. The chloroform extract is separated, washed with water,dried, and concentrated to give crudea-phenyl-ot-(2-pyridyl)-1-acetonaphthone;

M.P. 129' 132''c. following crystallization from ethanol. 1

The starting material is obtained as follows. A solution of 83 g. of2-benzylpyridine in 150 ml. of ether is added slowly to a solution ofphenyllithium (prepared from 7.5 g. of lithium and 85 g. of bromobenzenein 500 ml. of ether) and the mixture is stirred for one hour after theaddition is complete. A solution of 75 g. of lnaphthonitrile in 200 ml.of other is added and the mixture is heated under reflux for'12 hours,cooled and stirred with saturated ammonium chloride solution. The

ether layer is separated, combined with an ether extract of the aqueouslayer, washed with saturated sodium chloride solution, dried, andconcentrated to give a residue of crude2-[ot-(l-naphthirnidoyl)benzylJpyridine; M.P. 132- 135 C. followingcrystallization from methanol-benzene.

Example 6 A mixture of 3.0 g. of 2-[a-(2,4-dichlorobenzimidoyl)-benzy11pyridine and 30 ml. of 6 N sulfuric acid is heated under refluxwith stirring for 15 minutes. The mixture is cooled and the insolublesulfate salt of a-phenyI-a-(Z- pyridyl)-2,4-dichloroacetophenone iscollected on a filter; M.P. l84-186 C. following crystallization frommethanolether. The free base is obtained by stirring the sulfate saltwith 5% sodium hydroxide solution and extracting with ether.

The starting material is obtained as follows. A solution of 23 g. ofZ-benzylpyridine in 60 ml. of ether is added to a solution ofphenyllithium (prepared from 2.1 g. of lithium and 23 g. of bromobenzenein ml. of ether) and the mixture is heated under reflux for 50 minutesand then treated with a solution of 20 g. of 2,4- dichlorobenzonitrilein 100 ml. of tetrahydrofuran-ether. Heating under reflux is continuedfor live more hours and then 250 ml. of ice water is added and the etherphase is separated, washed with saturated sodium chloride solution,dried and evaporated under reduced pressure to give a residue of crude2-[tx-(2,4-dichlorobenzimidoyl)benzyl]- pyridine. For purification it isdissolved in ether, the solution chromatographed over alumina, and the.recov ered product crystallized from methanol; M.P. 114- 117 C. 1

Example 7 From 2- [a- (o-isopropylbenzimidoyl benzyl] pyridine, a-

phenyl-a-(Z-pyridyl) 2 isopropylacetophenone; M.P. 134-140 C.

I From 2-[u-(o-fluorobenzimidoyl)benzyl] pyridine, a-phen- From Z-[ct (otrifluoromethylbenzimidoyl)benzyl]pyridine, wphenyl-u-( 2 pyridyl) 2trifluoromethylacetophenone; M.P. 127-134 C.

From 2-[ot-(2,3-dichlorobenzimidoyl)benzyl]pyridine, 01

phenyl-a-(Z-pyridyl) 2,3 dichloroacetophenone; M.P.

From 2-[a-(2,6-dichlorobenzimidoyl)benzylJpyridine, u-

phenyl-ot-(2-pyridyl) 2,6 dichloroacetophenone; M.P. 148-151 C. From2-[a-(2,4-dimethylbenzimidoyl)benzyl]pyridine, a-

phenyl-a-(2-pyridyl) 2,4 dimethylacetophenone; the

sulfate salt melts at 193l95 C.

From 2-[a-(2,6-dimethylbenzirnidoyl)benzy1]pyridine, u-

phenyl-w(2-pyr1dyl)-2,6 dirnethylacetophenone; M.P. 148-152 C.

The 2- [a-(ortho-substituted benzimidoyDbenzylJpyridine compoundsemployed as starting materials are obtained by the reaction of thecorrespondingly substituted benzonitrile compounds with the lithiumderivative of 2- benzylpyridine under anhydrous condiitons followed bymild hydrolysis of the reaction mixture with water or am- Example 8 5 Asolution of 47 g. of Z-benzylpyridine in 100 ml. of anhydrous ether isadded to a solution of phenyllithium (prepared from 4.2 g. of lithiumand 47 g. of bromobenzene in 300 ml. of ether) and the mixture isstirred for one hour. The resulting solution containing the lithiumderivative of 2-benzylpyridine is treated with 40 g. of methylo-methylbenzoate in 100 ml. of anhydride ether and the mixture is heatedunder reflux for 12 hours, cooled and stirred with saturated ammoniumchloride solution. The ether phase is separated, washed, dried, andevaporated to give a residue ofa-phenyl-a-(Z-pyridyl)-2-methylacetophenone; M.P. l45-l49 C. followingcrystallization from methanol.

The same product is obtained by substituting 41 g. of o-methylbenzoylchloride for the methyl o-methylbenzoate in the foregoing procedure.

We claim:

1. A compound of the formula where AI is a member of the classconsisting of o-methylphenyl, o-ethylphenyl, o-isopropylphenyl,o-chlorophenyl, o-bromophenyl, o-fluorophenyl, o-methoxyphenyl,omethylthiophenyl, o-trifluoromethylphenyl, l-naphthyl, 2,3dichlorophenyl, 2,4 dichlorophenyl, 2,6 dichlorophenyl,2,4-dimethylphenyl and 2,6-dimethylphenyl.

2. a-Phenyl-a-(2-pyridyl)-2-methylacetophenone.

or.Pl16I1y1-oz-( Z-pyridyl)-2-chloroacetophenone. ct-PhEIlYl-a-(Z-pyridyl -2-bromoacetophenone.

3. 4. 5. u-Phenyl-a-(l-pyridyl)-2,4-dichloroacetophenone.

6. Process for the production of'compounds of the formula whichcomprises reacting a compound of the formula with a member of the classconsisting of strong acids and strong bases in a hydroxylic medium;where Ar is a member of the class consisting of o-methylphenyl,o-ethylphenyl, o-isopropylphenyl, o-chlorophenyl, o-bromophenyl,o-fluorophenyl, o-methoxyphenyl, o-methylthiophenyl,o-trifluorornethylphenyl, l-naphthyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,4-dimethylphenyl and2,6-dimethylphenyl.

7. Process according to claim 6 wherein the reaction is carried out witha strong acid and the strong acid is a mineral acid. 7

8. Process according to claim 6 wherein the hydroxylic medium is water.

9. Process according to claim 6 wherein the reaction is carried out witha strong acid and the product is isolated as the free base followingtreatment with a base.

OTHER REFERENCES Tilford et al.: JACS, vol. 76, p. 2439 (1954). Beckettet al.: J. Pharm. and Pharmacol., vol. 7, pp.

Levine et al.: (1960).

J. Org; Chem. vol. 25, pp. 530-7

1. A COMPOUND OF THE FORMULA 2.A-PHENYL-A-(2-PYRIDYL)-2-METHYLACETOPHENONE.